Ocular infectious disease in HIV infected individuals causes vision loss and in some cases total blindness in approximately 30% of patients. This is largely due to infectious viral retinitis. In addition, a retinal microvasculopathy causes multiple retinal infarctions in 70-100% of AIDS patients; this has recently been shown to cause a milder form of vision loss. This grant is a competitive renewal and focuses on four aspects of retinal disease: Epidemiology, Pathophysiology, Diagnostic modalities and New Therapies. The first goal is to further elucidate epidemiologic aspects and risk factors for retinal disease in HIV infected patients. The emphasis here is on retinal microvasculopathy as well as CMV retinitis. Virologic, immunologic and other data will be gathered on a cohort of well characterized HIV positive individuals enrolled in the 75 million dollar UCSD HIV Neurobehavioral Research Center. The pathophysiology of infectious and microvascular disease will be elucidated through a combination of clinical testing using new electrophysiological and psychophysical testing, and by prospective studies. We will determine the nature and extent of vision loss associated with retinal microvascular disease and infarctions of the inner retina (cotton wool spots). Studies of patients with risk factors for and complications of CMV retinitis will include studies to determine CD4 threshold for developing CMV retinitis and associations with CMV disease of the CNS. Additional studies will include risk factors for developing retinal detachment which appears to affect 20-25% of eyes with CMV retinitis. Laboratory investigations into pathophysiology will include confocal immunomicroscopic examination of whole mounted retina as well as PCR studies of retinal tissue from AIDS patients to elucidate further viral an other etiologies (cytokine related damage). Attempts to improve diagnostic abilities in patients with infectious retinal disease will include studies of the sensitivity and specificity of PCR, cultures and related techniques on ocular fluids and tissues obtained at autopsy as well as from clinical material. Finally, new approaches to therapy of infectious retinitis and its complications include randomized clinical trials of laser prophylaxis to prevent retinal detachment and combination foscarnet and ganciclovir therapy and a randomized trial of two surgical repair techniques for patients with retinal detachments. In the laboratory, we will pursue our studies of intravitreal injections of long acting anti-CMV compounds, one of which (HPMPC) has proven to be highly effective in an animal model of herpetic retinitis and which may be suitable for therapy in patients by intravitreal injection at infrequent intervals (once monthly).